PROCESS CREATION

(Synthesis and Design Alternatives)

1
 Objectives
On completing this part of the course, you should:
 Understand how to go about assembling design data and
creating a preliminary data base.
 Be able to implement the steps in creating flowsheets
involving reactions, separations, and T-P change operations.
In so doing, many alternatives are identified that can be
assembled into a synthesis tree that contains the most
promising alternatives.
 Know how to select the principal pieces of equipment and to
create a detailed process flowsheet, with a material and
energy balance and a list of major equipment items.

2 Process Creation
 Schedule - Process Creation
 Preliminary Database Creation
– to assemble data to support the design.
 Experiments
– often necessary to supply missing database items or verify
crucial data.
 Preliminary Process Synthesis
– top-down approach.
– to generate a “synthesis tree” of design alternatives.
– illustrated by the synthesis of processes for the
manufacture of VCM and tPA.
 Development of Base-case Design
– focusing on the most promising alternative(s) from the
synthesis tree.

Ref: Seider, Seader and Lewin (1999), Chapter 2

3 Process Creation
 Preliminary Database Creation
 Thermophysical property data
– physical properties
– phase equilibria (VLE data)
– Property prediction methods
 Environmental and safety data
– toxicity data
– flammability data
 Chemical Prices
– e.g. as published in the Chemical Marketing Reporter
 Experiments
– to check on crucial items above

4 Process Creation
 Literature and Information Sources
Company context - employees, company files, open literature
provide :
Product info (related), thermophysical properties, transport data,
flowsheets, equipment descriptions, process models.
National Laboratories and Research Institute Reports e.g. SRI
International, NIST, NIOSH.
Encyclopedias (technical, chemical process and technology).
Handbooks and Reference Books (Perry’s Chemical Engineer’s
Handbook, CRC Handbook of Physics and Chemistry)
Journals (Book format, electronic format)
Indexes (INSPEC, COMPENDEX, SCIENCE CITATION INDEX)
Patents (U.S. Patent Office www.uspto.gov/patft )
Auxiliary Studies (e.g. technical feasibility, marketing, business
related)
Innovation (e.g 3M)
5 Process Creation
 Preliminary Process Synthesis
Synthesis of chemical processes involves:
 Selection of processing mode: continuous or batch
 Fixing the chemical state of raw materials, products, and by-
products, noting the differences between them.
 Process operations (unit operations) - flowsheet building blocks
 Synthesis steps -
 Eliminate differences in molecular types
 Distribute chemicals by matching sources and sinks
 Eliminate differences in composition
 Eliminate differences in temperature, pressure and phase
 Integrate tasks (combine tasks into unit operations)

6 Process Creation
 Continuous or batch processing?

Continuous

Batch

Fed-batch

Batch-product removal

7 Process Creation
 The Chemical State
 Decide on the raw material and product specifications
(states):
 Mass (flow rate)
 Composition (mole or mass fraction of each chemical
species having a unique molecular type)
 Phase (solid, liquid, or gas)
 Form (e.g., particle-size distribution and particle shape)
 Temperature
 Pressure

8 Process Creation
 Process Operations (“Lego”)
 Chemical reaction
– Positioning in the flowsheet involves many considerations
(conversion, rates, etc.), related to T and P at which the
reaction are carried out.
 Separation of chemicals
– needed to resolve difference between the desired composition
of a product stream and that of its source. Selection of the
appropriate method depends on the differences of the physical
properties of the chemical species involved.
 Phase separation
 Change of temperature
 Change of pressure
 Change of phase
 Mixing and splitting of streams and branches

9 Process Creation
 Synthesis Steps

Synthesis Step Process Operation

 Eliminate differences in Chemical reaction
molecular types
 Distribute chemicals by Mixing
matching sources and sinks
 Eliminate differences in Separation
composition
 Eliminate differences in Temperature, pressure
temperature, pressure and and phase change
phase
 Integrate tasks (combine
tasks into unit operations)

10 Process Creation
 Process Creation

Example 1:

Vinyl Chloride Manufacture

11 Process Creation
  Eliminate differences in molecular types
Chemicals participating in VC Manufacture:
Molecular Chemical Chemical
Chemical weight formula structure

Acetylene 26.04 C2H2 H-CC-H

Chlorine 70.91 Cl2 Cl-Cl

Cl Cl
| |
H-C-C-H
1,2-Dichloroethane 98.96 C2H4Cl2 | |
H H
H H
C=C
Ethylene 28.05 C2H4 H H

Hydrogen chloride 36.46 HCl H-Cl

H Cl
C=C
Vinyl chloride 62.50 C2H3Cl H H

12 Process Creation
 Selection of pathway to VCM (1)
 Direct chlorination of ethylene:
C2H4  Cl2  C2H3Cl  HCl (2.1)
Advantages:
– Attractive solution to the specific problem denoted as
Alternative 2 in analysis of primitive problem.
– Occurs spontaneously at a few hundred oC.
Disadvantages:
– Does not give a high yield of VC without simultaneously
producing large amounts of by-products such as
dichloroethylene
– Half of the expensive chlorine is consumed to produce HCl by-
product, which may not be sold easily.

13 Process Creation
 Selection of pathway to VCM (2)
 Hydrochlorination of acetylene:

C2H2  HCl  C2H3Cl (2.2)

Advantages:
– This exothermic reaction is a potential solution for the specific
problem denoted as Alternative 3. It provides a good
conversion (98%) of C2H2 VC in the presence of HgCl2 catalyst
impregnated in activated carbon at atmospheric pressure.
– These are fairly moderate reaction conditions, and hence, this
reaction deserves further study.
Disadvantages:
– Flammability limits of C2H2 (2.5 100%)

14 Process Creation
 Selection of pathway to VCM (3)
 Thermal cracking of C2H4Cl2 from chlorination of C2H4:
C2H4  Cl2  C2H4Cl2 (2.3)
C H Cl  C H Cl  HCl (2.4)
2 4 2 2 3

C2H4  Cl2  C2H3Cl  HCl (2.1)

Advantages:
– Conversion of ethylene to 1,2-dichloroethane in exothermic
reaction (2.3) is 98% at 90 oC and 1 atm with a Friedel-Crafts
catalyst such as FeCl3. This intermediate is converted to vinyl
chloride by thermal cracking according to the endothermic
reaction (2.4), which occurs spontaneously at 500 oC with
conversions as high as 65% (Alternative 2).
Disadvantage:
– Half of the expensive chlorine is consumed to produce HCl
by-product, which may not be sold easily.
15 Process Creation
 Selection of pathway to VCM (4)
 Thermal Cracking of C2H4Cl2 from Oxychlorination of C2H4:
C2H4  2HCl  21 O2  C2H4Cl2  H2O (2.5)
C2H4Cl2  C2H3Cl  HCl (2.4)
C2H4  HCl  21 O2  C2H3Cl  H2O (2.6)
Advantages:
– Highly exothermic reaction (2.5) achieves a 95% conversion to
C2H4Cl2 in the presence of CuCl2 catalyst, followed by pyrolysis
step (2.4) as Reaction Path 3.
– Excellent candidate when cost of HCl is low
– Solution for specific problem denoted as Alternative 3.
Disadvantages:
– Economics dependent on cost of HCl

16 Process Creation
 Selection of pathway to VCM (5)
 Balanced Process for Chlorination of Ethylene:
C2H4  Cl2  C2H4Cl2 (2.3)
C2H4  2HCl  21 O2  C2H4Cl2  H2O (2.5)
2C2H4Cl2  2C2H3Cl  2HCl (2.4)
2C2H4  Cl2  21O2 2C2H3Cl  H2O (2.7)
Advantages:
– Combination of Reaction Paths 3 and 4 - addresses Alternative 2.
– All Cl2 converted to VC
– No by-products!

17 Process Creation
 Evaluation of Alternative Pathways

 Reaction Path  is eliminated due its low selectivity.

 This leaves four alternative paths, to be compared first in
terms of Gross Profit.

Chemical Bulk Prices

Chemical Cost (cents/lb)
Ethylene 18
Acetylene 50
Chlorine 11
Vinyl chloride 22
Hydrogen chloride 18
Water 0
Oxygen (air) 0

18 Process Creation
 Computing Gross Profit
Reaction path  C2H4 + Cl2 = C2H3Cl + HCl
lb-mole 1 1 1 1
Molecular weight 28.05 70.91 62.50 36.46
lb 28.05 70.91 62.50 36.46
lb/lb of vinyl chloride 0.449 1.134 1 0.583
cents/lb 18 11 22 18

Gross profit = 22(1) + 18(0.583) - 18(0.449) - 11(1.134) = 11.94 cents/lb VC

Reaction Gross Profit
Overall Reaction
Path (cents/lb of VC)
 C2H2 + HCl = C2H3Cl -9.33

 C2H4 +Cl2 = C2H3Cl + HCl 11.94

 C2H4 + HCl + O2 = C2H3Cl + H2O 3.42

 2C2H4 + Cl2 + O2 = 2C2H3Cl + H2O 7.68

19 Process Creation
 Preliminary Flowsheet for Path 

Cl2 HCl
113,400 lb/hr 58,300 lb/hr
Raw Materials C2H4Cl2 Products
Process Flowsheet?
HCl
C2H4,Direct
Cl2 Pyrolysis C2H3Cl, HCl
Chlorination
C2H3Cl
C2H4Cl2
C2H3Cl
C2H4 C2H4 + Cl2 C2H4Cl2 C2H4Cl2  C2H3Cl + HCl
100,000 lb/hr
44,900 lb/hr

 800 MM lb/year @ 330 days/y  100,000 lb/hr VC

 On the basis of this principal sink, the HCl sink and reagent
sources can be computed (each flow is 1,600 lbmol/h)
 Next step involves distributing the chemicals by matching
sources and sinks.

20 Process Creation
  Distribute the chemicals
 A conversion of 100% of the C2H4 is assumed in the chlorination
reaction.

21 Process Creation
  Distribute the chemicals
 Only 60% of the C2H4Cl2 is converted to C2H3Cl with a
byproduct of HCl, according to Eqn. (2.4).
 To satisfy the overall material balance, 158,300 lb/h of
C2H4Cl2 must produce 100,000 lb/h of C2H3Cl and 58,300 lb/h
of HCl.
 But a 60% conversion only produces 60,000 lb/h of VC.
 The additional C2H4Cl2 needed is computed by mass balance to
equal:
[(1 - 0.6)/0.6] x 158,300 or 105,500 lb/h.
 Its source is a recycle stream from the separation of C2H3Cl
from unreacted C2H4Cl2, from a mixing operation, inserted to
combine the two sources, to give a total 263,800 lb/h.

22 Process Creation
  Distribute the chemicals
 The effluent stream from the pyrolysis operation is the source
for the C2H3Cl product, the HCl by-product, and the C2H4Cl2
recycle.

23 Process Creation
  Distribute the chemicals
 Reactor pressure levels:
– Chlorination reaction: 1.5 atm is recommended, to eliminate the
possibility of an air leak into the reactor containing ethylene.
– Pyrolysis reaction: 26 atm is recommended by the B.F. Goodrich
patent (1963) without any justification. Since the reaction is
irreversible, the elevated pressure does not adversely affect
the conversion. Most likely, the patent recommends this
pressure to reduce the size of the pyrolysis furnace, although
the tube walls must be considerably thicker and many
precautions are necessary for operation at elevated pressures.
– The pressure level is also an important consideration in selecting
the separation operations, as will be discussed in the next
synthesis step.

24 Process Creation
  Eliminate Differences in Composition
 The product of the chlorination reaction is nearly pure
C2H4Cl2, and requires no purification.
 In contrast, the pyrolysis reactor conversion is only 60%, and
one or more separation operations are required to match the
required purities in the C2H3Cl and HCl sinks.
 One possible arrangement is given in the next slide. The data
below explains the design decisions made.
Boiling point (oC) Critical constants

Chemical 1 atm 4.8 atm 12 atm 26 atm Tc,C Pc, atm

HCl -84.8 -51.7 -26.2 0 51.4 82.1

C2H3Cl -13.8 33.1 70.5 110 159 56

C2H4Cl2 83.7 146 193 242 250 50

25 Process Creation
  Eliminate Boiling
Differences
point (oC) in Composition
Critical constants

Chemical 1 atm 4.8 atm 12 atm 26 atm Tc,C Pc, atm

HCl -84.8 -51.7 -26.2 0 51.4 82.1

C2H3Cl -13.8 33.1 70.5 110 159 56

C2H4Cl2 83.7 146 193 242 250 50

There may be other, possibly better alternative configurations,

26 Process Creation
  Eliminate differences in T, P and phase

27 Process Creation
  Integrate tasks (tasks  unit operations)

28 Process Creation
 Assembly of synthesis tree
Reaction Distribution Separations T, P and Task
path of chemicals phase integration
changes





Algorithmic methods are very effective for the synthesis,
analysis and
 optimization of alternative flowsheets.

29 Process Creation
 Development of Base-case Design
Develop one or two of the more promising flowsheets from the
synthesis tree for more detailed consideration.

30 Process Creation
 Process Creation

Example 2:

Manufacture of Tissue Plasmonigen Activator

31 DESIGN AND ANALYSIS II - (c) Daniel R. Lewin Process Creation

 Manufacture of tPA
tPA is tissue plasminogen activator
A recombinant, therapeutic protein
- comprised of 562 amino acids

32 DESIGN AND ANALYSIS II - (c) Daniel R. Lewin Process Creation

 Manufacture of tPA
Pharmacology:
 tPA activates plasminogen – to plasmin (an enzyme)
 plasmin dissolves fibrin formations that hold blood
clots in place
 blood flow is re-established once the clot blockage
dissolves
 important for patients with heart attacks
(myocardial infarction) or stroke
Business Strategy:
 has been produced by Genentech (ActivaseTM) since
1986
 sells for $2,000/100 mg dose
 2003 – Patent protection expires
 Design objective – manufacture generic form of
tPA to sell for $200/dose

33 DESIGN AND ANALYSIS II - (c) Daniel R. Lewin Process Creation

 Process Synthesis Problem

34 DESIGN AND ANALYSIS II - (c) Daniel R. Lewin Process Creation

  Eliminate differences in molecular types
Identify Reaction Paths – with help from the Biochemist

1. Mammalian Cells

tPA-DNA sequence + CHO cells  selected high expressing

PA-CHO cells (1)
(1-10 mg from (106 cells) (CHO cells with
human melanoma tPA-DNA inserted
cells) in their genomes)

Selected tPA-CHO cells (“founder cells”) amplified

to yield about 106 cells/mL – during R&D stage.
These cells are frozen into 1-mL aliquots at - 70C.

35 DESIGN AND ANALYSIS II - (c) Daniel R. Lewin Process Creation

  Eliminate differences in molecular types

Prepared in laboratory – stored in 1 mL aliquots at - 70°C

Used as inoculum for the bio-reaction:

tPA-CHO cells + HyQ PF-CHO media + O2

 Increased cell nos. (2)
0.39106 cells/mL-day
50 pg tPA/cell-day
0.210-12 mol O2/cell-hr

Rates from Genentech patent (1988)

As tPA-CHO cells reproduce, tPA secretes

into liquid media solution.

36 DESIGN AND ANALYSIS II - (c) Daniel R. Lewin Process Creation

 Computing Gross Profit
Project cost of chemicals produced or sold
Chemical Kg/Kg tPA Cost, $/Kg

tPA 1 2,000,000

HyQ PF CHO 287.2 233

powder media
Water for 2,228 0.12+
injection (WFI)
Air 46.8 1,742

CO2 3.7 1,447

tPA-CHO cells - *
 $200/100 mg dose
+ $0.45/gal = $450/1,000 gal
* Not included in gross profit estimate – related to cost of research, an operating cost.

37 DESIGN AND ANALYSIS II - (c) Daniel R. Lewin Process Creation

 Computing Gross Profit

Gross Profit = 2,000,000 – 287.2233 – 2,228 0.12

-3.7 1,447 – 46.8 1,742

= $1,846,000/Kg tPA

Does not include operating costs (cost of research

and cost of utilities) and investment cost

- yet, high for a pharmaceutical

- process synthesis proceeds at an accelerated pace

38 DESIGN AND ANALYSIS II - (c) Daniel R. Lewin Process Creation

 Insert Reaction Operations into Flowsheet

39 DESIGN AND ANALYSIS II - (c) Daniel R. Lewin Process Creation

  Distribute the chemicals

40 DESIGN AND ANALYSIS II - (c) Daniel R. Lewin Process Creation

  Eliminate Differences in Composition

tPA protein must be recovered from

other proteins, cell debris, media, water,
and gas emissions

Proteins lose activity (denature)

at temperatures above ~ 0C

Hence - entire separation process

designed to operate at 4C,
slightly above freezing point
of water.

41 DESIGN AND ANALYSIS II - (c) Daniel R. Lewin Process Creation

  Eliminate Differences in Composition

42 DESIGN AND ANALYSIS II - (c) Daniel R. Lewin Process Creation

  Eliminate differences in Temperature

43 DESIGN AND ANALYSIS II - (c) Daniel R. Lewin Process Creation

  Integrate tasks (tasks  unit operations)
 Equipment items are selected – often combining
operations into a single equipment item
 Key decision – batch or continuous operation
 80 Kg/yr tPA – batch mode
 Select equipment sizes to produce 1.6 Kg/batch
 i.e., 80/1.6 = 50 batch/yr
 To allow for separation losses, produce 2.24
Kg/batch in the cultivators
 Using 5,000 L vessel, 14 day/batch = cycle time
 Hence, run two batch trains in parallel
 each producing 25 batch/yr

44 DESIGN AND ANALYSIS II - (c) Daniel R. Lewin Process Creation

  Task Integration – Reactor Section

45 DESIGN AND ANALYSIS II - (c) Daniel R. Lewin Process Creation

  Task Integration – Separation Section

46 DESIGN AND ANALYSIS II - (c) Daniel R. Lewin Process Creation

 tPA - Synthesis Tree

47 DESIGN AND ANALYSIS II - (c) Daniel R. Lewin Process Creation

 Process Creation - Summary
 Preliminary Database Creation
– needed to provide data to support the design.
 Experiments
– often necessary to supply missing database items or verify
crucial data.
 Preliminary Process Synthesis
– top-down approach.
– generates a “synthesis tree” of design alternatives.
– illustrated by the synthesis of the VCM and tPA processes.
 Development of Base-case Design
– focusing on the most promising alternative(s) from the
synthesis tree.

Next week: Process Design Heuristics

48 DESIGN AND ANALYSIS II - (c) Daniel R. Lewin Process Creation